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首页> 外文期刊>Journal of Neuroscience Research >The antiviral cytokine interferon-gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation
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The antiviral cytokine interferon-gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation

机译：抗病毒细胞因子干扰素-γ通过激活Dat1和调制视网膜母细胞瘤蛋白磷酸化来限制神经茎/祖细胞增殖

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摘要

Neural stem/progenitor cells (NPSCs) express receptors for many inflammatory cytokines, with varying effects on differentiation and proliferation depending on the stage of development and the milieu of inflammatory mediators. In primary neurons and astrocytes, we recently showed that interferon gamma (IFN), a potent antiviral cytokine that is required for the control and clearance of many central nervous system (CNS) infections, could differentially affect cell survival and cell cycle progression depending upon the cell type and the profile of activated intracellular signaling molecules. Here, we show that IFN inhibits proliferation of primary NSPCs through dephosphorylation of the tumor suppressor Retinoblastoma protein (pRb), which is dependent on activation of signal transducers and activators of transcription-1 (STAT1) signaling pathways. Our results show i) IFN inhibits neurosphere growth and proliferation rate in a dose-dependent manner; ii) IFN blocks cell cycle progression through a late-stage G1/S phase restriction; iii) IFN induces phosphorylation and expression of STAT1 and STAT3; iv) IFN decreases cyclin E/cdk2 expression and reduces phosphorylation of cyclin D1 and pRb on serine residue 795; and v) the effects of IFN on NSPC proliferation, cell cycle protein expression, and pRb phosphorylation are STAT1-dependent. These data define a mechanism by which IFN could contribute to a reduction in NSPC proliferation in inflammatory conditions. Further delineation of the effects of inflammatory cytokines on NSPC growth could improve our understanding of how CNS infections and other inflammatory events disrupt brain development and NSPC function. (c) 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
机译：神经茎/祖细胞（NPSCS）表达许多炎性细胞因子的受体，根据发育阶段和炎症介质的Milieu，对分化和增殖的不同影响。在原发性神经元和星形胶质细胞中，我们最近显示干扰素γ（IFN），对许多中枢神经系统（CNS）感染的控制和清除所需的有效的抗病毒细胞因子可以差异地影响细胞存活和细胞周期进展，这取决于细胞类型和活化细胞内信号分子的轮廓。在这里，我们表明IFN通过肿瘤抑制视网膜母细胞瘤蛋白（PRB）的磷酸化抑制原发性NSPC的增殖，这取决于信号传感器和转录-1（STAT1）信号传导途径的激活剂的激活。我们的结果表明I）IFN以剂量依赖的方式抑制神经圈生长和增殖率; ii）IFN通过晚期G1 / S相限制阻断细胞周期进展; III）IFN诱导STAT1和Stat3的磷酸化和表达; IV）IFN降低了细胞周期蛋白E / CDK2表达，并减少了细胞周期蛋白D1和PRB的磷酸硅酸盐795; v）IFN对NSPC增殖，细胞周期蛋白表达和PRB磷酸化的影响是统计的。这些数据定义了IFN可以有助于降低炎症条件下的NSPC增殖的机制。进一步描绘炎性细胞因子对NSPC生长的影响可以改善我们对CNS感染和其他炎症事件破坏脑发展和NSPC功能的理解。 （c）2016年作者。威利期刊（Inc）发表的神经科学研究杂志

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